Project Summary Transcatheter Aortic Valve Replacement (TAVR) has emerged as a life-saving solution for inoperable elderly patients with calcific aortic valve disease (CAVD) and severe Aortic Stenosis (AS). However, in recent years certain limitations and serious adverse events emerged: failed delivery due to tortuous aortic geometry and severe valvular calcification, valve migration, conduction abnormalities, and paravalvular leaks (PVL) leading to embolization with increased stroke risk, increasing the overall morbidity and mortality post-TAVR. Current TAVR technology is based on tissue valves adapted to, but not specifically designed for TAVR. Those may sustain damage during crimping and deployment, resulting in limited durability and impaired functionality. In latest-generation TAVR devices ad hoc solutions to reduce PVL have been associated with higher incidence of cardiac conduction abnormalities (CCAs), often leading to the need for concurrent permanent pacemaker implantation. This may limit TAVR utility and its anticipated expansion into younger, lower risk patients, including a BAV (bicuspid aortic valve) patients, in which off-label use of TAVR is rapidly emerging. Given the aging U.S. population segment at high risk for AS that is expected to double by mid-century, there is a critical need for optimizing the procedure and developing long-term TAVR technology ? optimized to reduce the complications rates while achieving better clinical outcomes. Our translational project aims to develop next generation TAVR technology. Combining imaging, computational, and in vitro tools in a refined biomechanical analysis methodology, an optimization approach will guide the pre-planning and tailor TAVR procedures for achieving significantly better patient outcomes and reduce ensuing complications. We also aim to offer a disruptive technology: next generation valves specifically optimized for TAVR. The Polynova polymeric valve was developed using our design optimization DTE methodology under a U01 Quantum project and a current STTR award. It incorporates a novel xSIBS hemcompatible polymer with better tolerance to crimping and deployment stresses, improved hemodynamic performance and thromboresistance, and extended durability. Its TAVR prototypes will be rigorously tested and further optimized. These goals will be achieved by employing an innovative Reverse Calcification Technique (RCT) to predict CAVD Progression. We will use patient specific reconstructed geometries from a large CAVD patient?s database as input for refined numerical simulations. We will expand our existing large CT scans database of CAVD patients (currently n=750), as well as utilize TAVR databases from two additional medical centers (n=293 and 94, respectively), to catalog the disease progression to further serve to elucidate, plan and predict interventional outcomes. Using RCT as a base for predictive models of prospective calcification growth ? both in tricuspid (TAV) and bicuspid CAVD patients, we will employ a combined in silico and in vitro biomechanical analysis that will include detailed and refined structural, FSI (Fluid Structure Interaction) and CFD (Computational Fluid Dynamics) simulations in the patient specific geometries reconstructed from CT scans. Heterogeneous tissue and AVC components properties will be obtained by biomechanical testing of specimens from surgical CAVD patients. Multiscale tissue and calcification modeling will utilize input derived from micro-CT measurements to fine tune the models. Various CAVD stages will be studied with FSI based on the RCT models, and validated with hemodynamics measurements in a ViVitro left heart simulator (LHS) and in fabricated 3D printed model replicas of CAVD patients in the Vascular Simulations Replicator system, with follow-up thrombogenicity measurements in flow loops powered by a Berlin left ventricular assist device and SynCardia total artificial heart. We will fine-tune the in vitro hemodynamic and durability of the Polynova polymeric TAVR valve using the above approaches, as well a ViVitro Hi-Cycle system, and develop a dedicated design for BAV patients addressing deployment and valve eccentricity issues. Using in silico modeling with the Living Heart Human Model (LHHM), we will evaluate tissue strains that is predictive of CCAs and atrioventricular blockage associated with TAVR deployment, and compare successful TAVR cases to those with CCAs and pacemaker implantation. Finally, we will study the in vitro and in silico efficacy of pre-adherent polymeric biomaterials applied to TAVR stents in reducing eccentricity and sealing PVL.